Extension of Life Span in Normal Human Cells by Telomerase Activation: A Revolution in Cultural Senescence

Normal human cells have a limited life span in culture, exhaust their replicative potential after a fixed number of doublings, and enter a phase of cell cycle arrest termed "senescence(definition)." Senescent cells are metabolically active cells, known to up-regulate several cyclin-dependent kinase inhibitors and to be arrested primarily at the G1 phase of cell cycle. Telomere(definition) loss due to incomplete replication of the ends in normal somatic cells is thought to be the signal which initiates the senescence cascade. Lack of telomere maintenance in somatic cells may be caused by the absence or the low enzymatic activity of telomerase, the enzyme responsible for synthesis of telomeric DNA that counteracts the end-replication problem. Previous attempts to increase the life span of human cells involved inactivation of tumor suppressor genes such as p53 were not a viable method of life span extension because of significant risk of genomic instability. Extension of the life span of normal cells with minimal risk of genetic instability may be achieved by manipulation of the most upstream signals that initiate the senescence cascade. We and others have recently shown that reactivation of telomerase in normal human cells leads to restoration of the length of telomeric DNA and to a highly significant increase in cellular life span. These data provide strong evidence consistent with the telomere hypothesis and indicate that elongation of telomere length by genetic manipulation might render normal human cells virtually immortal. These findings indicate that telomere shortening and senescence act as a tumor suppressor mechanism and establish a solid genetic link between telomeres, cellular aging, and immortalization.